Rapid decline in the susceptibility of Plasmodium falciparum to dihydroartemisinin–piperaquine in the south of Vietnam

Abstract

BackgroundArtemisinin resistant Plasmodium falciparum has emerged in the countries of the Greater Mekong sub-region posing a serious threat to global malaria elimination efforts. The relationship of artemisinin resistance to treatment failure has been unclear.MethodsIn annual studies conducted in three malaria endemic provinces in the south of Vietnam (Binh Phuoc, Ninh Thuan and Gia Lai) between 2011 and 2015, 489 patients with uncomplicated P. falciparum malaria were enrolled in detailed clinical, parasitological and molecular therapeutic response assessments with 42 days follow up. Patients received the national recommended first-line treatment dihydroartemisinin-piperaquine for three days.ResultsOver the 5 years the proportion of patients with detectable parasitaemia on day 3 rose steadily from 38 to 57% (P < 0.001). In Binh Phuoc province, the parasite clearance half-life increased from 3.75 h in 2011 to 6.60 h in 2015 (P < 0.001), while treatment failures rose from 0% in 2012 and 2013, to 7% in 2014 and 26% in 2015 (P < 0.001). Recrudescence was associated with in vitro evidence of artemisinin and piperaquine resistance. In the treatment failures cases of 2015, all 14 parasite isolates carried the C580Y Pfkelch 13 gene, marker of artemisinin resistance and 93% (13/14) of them carried exoE415G mutations, markers of piperaquine resistance.ConclusionsIn the south of Vietnam recent emergence of piperaquine resistant P. falciparum strains has accelerated the reduced response to artemisinin and has led to treatment failure rates of up to 26% to dihydroartemisinin-piperaquine, Vietnam’s current first-line ACT. Alternative treatments are urgently needed.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-017-1680-8) contains supplementary material, which is available to authorized users.

K13 Propeller Mutations in Plasmodium falciparum Populations in Regions of Malaria Endemicity in Vietnam from 2009 to 2016

“…falciparum malaria among the total number of cases of malaria in those regions. The clinical impact of this genetic change has been high: the appropriate clinical and parasitological response (APCR) rates for DP treatment were 93% and 86% in 2010 (13) and 2014, respectively, but the rate dropped to 78% in 2015 (14). The results of the present study confirm the spread of the phenotype with a long clearance half-life as well as an increase in the frequency of various K13 genotypes.…”

Genetic markers of artemisinin resistance in Plasmodium spp. parasites

“…Firstly, parasite persistence and slow clearance in African studies are not associated with the pfk13 polymorphism [10,21]. Secondly, K13 variants do not determine parasite recurrence after treatment with the ACT DHA-piperaquine (DP), as recently reported for three sites in Vietnam [17]. The Gia Lai site, in which 67% of P. falciparum malaria patients carried the C580Y variant of pfk13, showed 89% treatment success ('adequate clinical and parasitological response', ACPR), whereas the ACPR among patients enrolled at Ninh Thuan was 78% (C580Y prevalence rate 4%), and among patients enrolled at Binh Phuoc, the ACPR was a very disappointing 56% (C580Y prevalence rate 73%).…”

“…The Gia Lai site, in which 67% of P. falciparum malaria patients carried the C580Y variant of pfk13, showed 89% treatment success ('adequate clinical and parasitological response', ACPR), whereas the ACPR among patients enrolled at Ninh Thuan was 78% (C580Y prevalence rate 4%), and among patients enrolled at Binh Phuoc, the ACPR was a very disappointing 56% (C580Y prevalence rate 73%). In fact, the best interpretation of this study is that it is falling partner drug efficacy that has led to the low ACPR in some sites [17]. Furthermore, in Myanmar, despite a prevalence rate of 25-65% of the C580Y variant pfk13 in 2012 and 2013 in Kawthaung and Myawaddy, 3 days of standard ACT delivered ≥96% ACPR [22].…”

“…There is considerable concern that, faced with the spread of pfk13 variants to the wider GMS, the proportion of slow-clearing phenotypes is increasing, thus posing an immediate threat to ACT efficacy within the region and more globally in the future [17][18][19][20]. In fact, some authors have called on the WHO to declare artemisinin 'resistance' to be a ''public health emergency of international concern' [18].…”

Rapamycin promotes the anticancer action of dihydroartemisinin in breast cancer MDA-MB-231 cells by regulating expression of Atg7 and DAPK

“…Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin (ARS) isolated from the traditional Chinese herb Artemisia annua L.; it has been frequently used in the treatment of malaria (1,2). Previous studies have reported that DHA also has potent antitumor effects; however, its anticancer mechanism is not well understood (3)(4)(5)(6).…”